Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping

Abstract

Objective: To determine, in patients identified as seropositive for neuronal voltage-gated potassium channel (VGKC) complex autoantibodies, the spectrum of clinical presentations and frequency of leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) as defined antigenic neuronal targets in the VGKC macromolecular complex.

Design: Retrospective cohort study.

Setting: Clinical practice, Mayo Clinic Neuroimmunology Laboratory and Department of Neurology.

Patients: A total of 54 853 patients were evaluated, of whom 1992 were found to be VGKC complex IgG positive.

Results: From June 1, 2008, to June 30, 2010, comprehensive service serologic evaluation performed on 54853 patients with unexplained neurologic symptoms identified 1992 patients (4%) who were positive for VGKC complex IgG (values ≥ 0.03 nmol/L). Among 316 seropositive patients evaluated clinically at our institution, 82 (26%) were seropositive for LGI1 IgG and/or CASPR2 IgG. Of these 82 patients, 27% had low (0.03-0.09 nmol/L), 51% had medium (0.10-0.99 nmol/L), and 22% had high (≥ 1.00 nmol/L) VGKC complex IgG values. Leucine-rich glioma-inactivated protein 1 IgG positivity was associated with higher VGKC complex IgG values (P< .001) and cortical presentations (P< .001); CASPR2 IgG was associated with peripheral motor excitability (P= .009). However, neither autoantibody was pathognomonic for a specific neurologic presentation or correlated significantly with cancer. Neurologic phenotypes were diverse. Cerebrocortical manifestations (including cognitive impairment and seizures) were recorded in 76% of patients with LGI1 IgG alone (n=46) and 29% with CASPR2 IgG alone (n=28). Peripheral motor hyperexcitability was found in 21% of patients with CASPR2 IgG alone and 6.5% of patients with LGI1 IgG alone.

Conclusions: The study emphasizes diverse and overlapping neurologic phenotypes across a range of VGKC complex IgG values and varying LGI1 IgG and CASPR2 IgG specificities. The frequent occurrence of LGI1 IgG and CASPR2 IgG in serum samples with low and medium VGKC complex IgG values supports the clinical significance of low values in clinical evaluation. Additional antigenic components of VGKC macromolecular complexes remain to be defined.

Figure

Voltage-gated potassium channel (VGKC) values and frequency of contactin-associated protein-like 2 (CASPR2) IgG and leucine-rich glioma-inactivated protein 1 (LGI1) IgG detection. Voltage-gated potassium channel complex IgG binds to LGI1 or CASPR2 in only a minority of cases. The frequency of LGI1 IgG and CASPR2 IgG detection by cell-binding assay stratified into 3 subgroups based on VGKC complex IgG values shows a range of values associated with CASPR2 IgG and LGl1 IgG detection. A, The VGKC complex IgG values (y-axis) of patients identified as positive for CASPR2 IgG (green circles), LGI1 IgG (red circles), both CASPR2 IgG and LGI1 IgG (blue circles), or negative for both (black dots). The dashed line indicates the frequency of LGI1 IgG and/or CASPR2 IgG in seropositive patients whose VGKC complex IgG values exceed or are less than 0.40 nmol/L. B, The percentage of subtyped antibodies based on VGKC complex IgG values.